[Reports] SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19
Although coronavirus disease 2019 (COVID-19) causes cardiac dysfunction in up to 25% of patients, its pathogenesis remains unclear. Exposure of human induced pluripotent stem cell (iPSC)–derived heart cells to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed productive infection and robust transcriptomic and morphological signatures of damage, particularly in cardiomyocytes. Transcriptomic disruption of structural genes corroborates adverse morphologic features, which included a distinct pattern of myofibrillar fragmentation and nuclear disruption. Human autopsy specimens from patients with COVID...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Perez-Bermejo, J. A., Kang, S., Rockwood, S. J., Simoneau, C. R., Joy, D. A., Silva, A. C., Ramadoss, G. N., Flanigan, W. R., Fozouni, P., Li, H., Chen, P.-Y., Nakamura, K., Whitman, J. D., Hanson, P. J., McManus, B. M., Ott, M., Conklin, B. R., McDevitt, Tags: Reports Source Type: research
[Research Articles] T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals
Long-term immunological memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for the development of population-level immunity, which is the aim of vaccination approaches. Reports on rapidly decreasing antibody titers have led to questions regarding the efficacy of humoral immunity alone. The relevance of T cell memory after coronavirus disease 2019 (COVID-19) remains unclear. Here, we investigated SARS-CoV-2 antibody and T cell responses in matched samples of COVID-19 convalescent individuals up to 6 months after infection. Longitudinal analysis revealed decreasing and stable spike- and nucleoc...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Bilich, T., Nelde, A., Heitmann, J. S., Maringer, Y., Roerden, M., Bauer, J., Rieth, J., Wacker, M., Peter, A., Hörber, S., Rachfalski, D., Märklin, M., Stevanovic, S., Rammensee, H.-G., Salih, H. R., Walz, J. S. Tags: Research Articles Source Type: research
[Research Articles] Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents
Subcortical white matter stroke (WMS) accounts for up to 30% of all stroke events. WMS damages primarily astrocytes, axons, oligodendrocytes, and myelin. We hypothesized that a therapeutic intervention targeting astrocytes would be ideally suited for brain repair after WMS. We characterize the cellular properties and in vivo tissue repair activity of glial enriched progenitor (GEP) cells differentiated from human-induced pluripotent stem cells, termed hiPSC-derived GEPs (hiPSC-GEPs). hiPSC-GEPs are derived from hiPSC–neural progenitor cells via an experimental manipulation of hypoxia inducible factor activity by brie...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Llorente, I. L., Xie, Y., Mazzitelli, J. A., Hatanaka, E. A., Cinkornpumin, J., Miller, D. R., Lin, Y., Lowry, W. E., Carmichael, S. T. Tags: Research Articles Source Type: research
[Research Articles] The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia
Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia tha...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Sweeney, P., Bedenbaugh, M. N., Maldonado, J., Pan, P., Fowler, K., Williams, S. Y., Gimenez, L. E., Ghamari-Langroudi, M., Downing, G., Gui, Y., Hadley, C. K., Joy, S. T., Mapp, A. K., Simerly, R. B., Cone, R. D. Tags: Research Articles Source Type: research
[Research Articles] Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents
Fetal lung underdevelopment, also known as pulmonary hypoplasia, is characterized by decreased lung growth and maturation. The most common birth defect found in babies with pulmonary hypoplasia is congenital diaphragmatic hernia (CDH). Despite research and clinical advances, babies with CDH still have high morbidity and mortality rates, which are directly related to the severity of lung underdevelopment. To date, there is no effective treatment that promotes fetal lung growth and maturation. Here, we describe a stem cell–based approach in rodents that enhances fetal lung development via the administration of extracel...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Antounians, L., Catania, V. D., Montalva, L., Liu, B. D., Hou, H., Chan, C., Matei, A. C., Tzanetakis, A., Li, B., Figueira, R. L., da Costa, K. M., Wong, A. P., Mitchell, R., David, A. L., Patel, K., De Coppi, P., Sbragia, L., Wilson, M. D., Rossant, J., Tags: Research Articles Source Type: research
[Research Articles] Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial
Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibiti...
Source: Science Translational Medicine - April 21, 2021 Category: Biomedical Science Authors: Le Lay, J. E., Du, Q., Mehta, M. B., Bhagroo, N., Hummer, B. T., Falloon, J., Carlson, G., Rosenbaum, A. I., Jin, C., Kimko, H., Tsai, L.-F., Novick, S., Cook, B., Han, D., Han, C. Y., Vaisar, T., Chait, A., Karathanasis, S. K., Rhodes, C. J., Hirshberg, Tags: Research Articles Source Type: research
[Research Articles] Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma
Malignant pleural mesothelioma (MPM) is an intractable disease with an extremely poor prognosis. Our clinical protocol for MPM of subablative radiotherapy (RT) followed by radical surgery achieved better survival compared to other multimodal treatments, but local relapse and metastasis remain a problem. This subablative RT elicits an antitumoral immune response that is limited by the immunosuppressive microenvironment generated by regulatory T (Treg) cells. The antitumor effect of immunotherapy to simultaneously modulate the immune activation and the immune suppression after subablative RT has not been investigated in MPM....
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Murakami, J., Wu, L., Kohno, M., Chan, M.-L., Zhao, Y., Yun, Z., Cho, B. C. J., de Perrot, M. Tags: Research Articles Source Type: research
[Research Articles] Imaging Enterobacterales infections in patients using pathogen-specific positron emission tomography
Enterobacterales represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-sorbitol (18F-FDS) can selectively detect Enterobacterales infections in murine models. Here,...
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Ordonez, A. A., Wintaco, L. M., Mota, F., Restrepo, A. F., Ruiz-Bedoya, C. A., Reyes, C. F., Uribe, L. G., Abhishek, S., DAlessio, F. R., Holt, D. P., Dannals, R. F., Rowe, S. P., Castillo, V. R., Pomper, M. G., Granados, U., Jain, S. K. Tags: Research Articles Source Type: research
[Research Articles] Brain injury instructs bone marrow cellular lineage destination to reduce neuroinflammation
Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predom...
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Shi, S. X., Shi, K., Liu, Q. Tags: Research Articles Source Type: research
[Research Articles] Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia
This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents. (Source: Science Translational Medicine)
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Crickx, E., Chappert, P., Sokal, A., Weller, S., Azzaoui, I., Vandenberghe, A., Bonnard, G., Rossi, G., Fadeev, T., Storck, S., Fadlallah, J., Meignin, V., Riviere, E., Audia, S., Godeau, B., Michel, M., Weill, J.-C., Reynaud, C.-A., Mahevas, M. Tags: Research Articles Source Type: research
[Reports] Lessons from applied large-scale pooling of 133,816 SARS-CoV-2 RT-PCR tests
Pooling multiple swab samples before RNA extraction and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis has been proposed as a strategy to reduce costs and increase throughput of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. However, reports on practical large-scale group testing for SARS-CoV-2 have been scant. Key open questions concern reduced sensitivity due to sample dilution, the rate of false positives, the actual efficiency (number of tests saved by pooling), and the impact of infection rate in the population on assay performance. Here, we report an analysis of 133,8...
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Barak, N., Ben-Ami, R., Sido, T., Perri, A., Shtoyer, A., Rivkin, M., Licht, T., Peretz, A., Magenheim, J., Fogel, I., Livneh, A., Daitch, Y., Oiknine-Djian, E., Benedek, G., Dor, Y., Wolf, D. G., Yassour, M., The Hebrew University-Hadassah COVID-19 Diagn Tags: Reports Source Type: research
[Research Articles] Using viral load and epidemic dynamics to optimize pooled testing in resource-constrained settings
Virological testing is central to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containment, but many settings face severe limitations on testing. Group testing offers a way to increase throughput by testing pools of combined samples; however, most proposed designs have not yet addressed key concerns over sensitivity loss and implementation feasibility. Here, we combined a mathematical model of epidemic spread and empirically derived viral kinetics for SARS-CoV-2 infections to identify pooling designs that are robust to changes in prevalence and to ratify sensitivity losses against the time course of individ...
Source: Science Translational Medicine - April 14, 2021 Category: Biomedical Science Authors: Cleary, B., Hay, J. A., Blumenstiel, B., Harden, M., Cipicchio, M., Bezney, J., Simonton, B., Hong, D., Senghore, M., Sesay, A. K., Gabriel, S., Regev, A., Mina, M. J. Tags: Research Articles Source Type: research
[Research Articles] Ultrasensitive point-of-care immunoassay for secreted glycoprotein detects Ebola infection earlier than PCR
Ebola virus (EBOV) hemorrhagic fever outbreaks have been challenging to deter due to the lack of health care infrastructure in disease-endemic countries and a corresponding inability to diagnose and contain the disease at an early stage. EBOV vaccines and therapies have improved disease outcomes, but the advent of an affordable, easily accessed, mass-produced rapid diagnostic test (RDT) that matches the performance of more resource-intensive polymerase chain reaction (PCR) assays would be invaluable in containing future outbreaks. Here, we developed and demonstrated the performance of a new ultrasensitive point-of-care imm...
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Fontes, C. M., Lipes, B. D., Liu, J., Agans, K. N., Yan, A., Shi, P., Cruz, D. F., Kelly, G., Luginbuhl, K. M., Joh, D. Y., Foster, S. L., Heggestad, J., Hucknall, A., Mikkelsen, M. H., Pieper, C. F., Horstmeyer, R. W., Geisbert, T. W., Gunn, M. D., Chilk Tags: Research Articles Source Type: research
[Research Articles] Widespread and sustained target engagement in Huntingtons disease minipigs upon intrastriatal microRNA-based gene therapy
This study demonstrates widespread biodistribution, strong and durable efficiency of rAAV5-miHTT in disease-relevant regions in a large brain, and the potential of using CSF analysis to determine vector expression and efficacy in the clinic. (Source: Science Translational Medicine)
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Valles, A., Evers, M. M., Stam, A., Sogorb-Gonzalez, M., Brouwers, C., Vendrell-Tornero, C., Acar-Broekmans, S., Paerels, L., Klima, J., Bohuslavova, B., Pintauro, R., Fodale, V., Bresciani, A., Liscak, R., Urgosik, D., Starek, Z., Crha, M., Blits, B., Pe Tags: Research Articles Source Type: research
[Research Articles] A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma
Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)–specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T ...
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Yang, W., Feng, Y., Zhou, J., Cheung, O. K.-W., Cao, J., Wang, J., Tang, W., Tu, Y., Xu, L., Wu, F., Tan, Z., Sun, H., Tian, Y., Wong, J., Lai, P. B.-S., Chan, S. L., Chan, A. W.-H., Tan, P. B.-O., Chen, Z., Sung, J. J.-Y., Yip, K. Y.-L., To, K.-F., Cheng Tags: Research Articles Source Type: research
